Our group focuses on genetic variants that disrupt molecular functions that cause human disease. In this renewal R01 application, we propose to begin the process of realizing our long-term goals, and to expand our original scope of research to include the challenge of understanding genetic disease mutations and polymorphisms that affect gene expression regulation in noncoding regions. Additionally, we have formed collaborations with genetic data managers and will apply these methods to aid in their research and identify new testable hypotheses. We will do this in three aims. First, we will integrate predictions of protein-disease associations with mutation predictions to develop a new quantitative model of genotype and phenotype. Second, we will integrate each of these together to develop a systems level, molecular function genome annotator with functionality to import into the genome databases. Finally, we will continue to build new methods for characterization of mutations using sequence, function and structure and begin testing our published hypotheses. Each of these aims will include collaboration with the maintainers of genetic datasets to better understand their underlying molecular effects.